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Pharmaceutical compositions comprising chelidonine or derivatives thereof

a technology of chelidonine and composition, applied in the direction of drug composition, biocide, cardiovascular disorder, etc., can solve the problems of abnormal cardiac impulse formation or impulse propagation, less effective heart pump, and use of drugs to manage cardiac arrhythmias

Inactive Publication Date: 2005-05-03
EUN JAE SOON +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Arrhythmias are abnormal rhythms of the heart and cause the heart to pump less effectively.
At this time, electro-biochemical properties on local regions of cardiac muscle are changed due to a variety of causes, and thus abnormal cardiac impulse formation or impulse propagation occurs.
A major obstacle to the widespread use of drugs to manage cardiac arrhythmias has been a relatively high incidence of extracardiac side effects.
However, cardiac side effects, which often arise as a direct consequence of drugs' antiarrhythmic mechanisms, have been very difficult to be circumvented.
However, these drugs also produce various side effects as described above, which limits their clinical applications.
However, drugs satisfying the above requirements have not yet been developed.
However, these drugs are known to have various side effects due to their lack of selectivity for ion channels.

Method used

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  • Pharmaceutical compositions comprising chelidonine or derivatives thereof
  • Pharmaceutical compositions comprising chelidonine or derivatives thereof
  • Pharmaceutical compositions comprising chelidonine or derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

example 5

Preparation of {[5bR-(5bα,6β,12bα)]-5b,6,7,12b,13,14-hexahydro-13-methyl[1,3]benzodioxolo[5,6c]-1,3-dioxolo[4,5-i]phenanthridin-6-yl}-methanesulfonate (compound 10)

[0108]Chelidonine (18 mg, 0.048 mmol) was dissolved in anhydrous methylene dichloride (0.5 ml), and then stirred at 0° C. for 10 minutes. Anhydrous triethylamine (8 μl, 0.058 mmol) and methanesulfonyl chloride (6 μl, 0.073 mmol) were added to the solution, and stirred at room temperature for 6 hours. The resulting reaction solution was extracted with ethylacetate, washed, dried, and purified by column chromatography (hexane:ethylacetate=2:1) to prepare 16 mg (77%) of the title compound (compound 10).

[0109]Rf=0.39 (hexane:ethylacetate=2:1)

[0110]1H-NMR (500 MHz, CDCl3): δ 7.21 (d, 1H, J=8.0 Hz), 7.18 (s, 1H), 6.69 (d, 1H, J=8.5 Hz), 6.42 (s, 1H), 5.90 (d, 2H, J=5.0 Hz), 5.88 (d, 2H, J=15.5 Hz), 5.18-5.16 (m, 1H), 4.13-4.11 (m, 1H), 3.75 (s, 1H), 3.73 (d, 2H, J=12 Hz), 3.45 (d, 2H, J=17 Hz), 3.14-3.08 (m, 1H), 3.05 (s, 3H), ...

example 6

Preparation of {[5bR-(5bα,6β,12bα)]-5b,6,7,12b,13,14-hexahydro-13-methyl[1,3]benzodioxolo[5,6c]-1,3-dioxolo[4,5-i]phenanthridin-6-yl}-4-methylbenzenesulfonate (Compound 11)

[0111]A solution of chelidonine (10 mg, 0.027 mmol) in anhydrous methylene dichloride (0.3 ml) was stirred at 0° C. for 10 minutes. Anhydrous triethylamine (5 μl, 0.032 mmol) and paratoluenesulfonyl chloride (8 μl, 0.040 mmol) were added to the solution, and stirred at room temperature for 12 hours. The resulting reaction solution was extracted with ethylacetate, washed, dried, and purified by column chromatography (hexane:ethylacetate=2:1) to prepared 8.6 mg (63%) of the title compound (compound 11).

[0112]Rf=0.36 (hexane:ethylacetate=2:1)

[0113]1H-NMR (500 MHz, CDCl3): δ 7.86 (d, 2H, J=8.5 Hz), 7.37 (d, 2H, J=8.5 Hz), 7.30-7.26 (m, 1H), 7.20 (s, 1H), 6.66 (d, 2H, J=8.0 Hz), 6.33 (s, 1H), 5.89 (d, 2H, J=3.5 Hz), 5.87 (d, 2H, J=18 Hz), 4.96-4.92 (m, 1H), 4.03 (d, 1H, J=5.0 Hz), 3.67 (d, 2H, J=17.5 Hz), 3.60 (bs, 1H)...

example 7

Preparation of {[5bR-(5bα,6β,12bα)]-5b,6,7,12b,13,14-hexahydro-13-[1,3]benzodioxolo[5,6c]-1,3-dioxolo[4,5-i]phenanthridin-6-yl}-carbamate (Compound 12)

[0114]A solution of sodium carbonate (10 mg, 0.097 mmol) and chlorosulfonyl isocyanate (6 μl, 0.065 mmol) in anhydrous methylene dichloride (0.4 ml) was stirred at −78° C. for 10 minutes. A solution of chelidonine (20 mg, 0.054 mmol) in anhydrous methylene dichloride (0.14 ml) was added dropwise to the reaction solution. After the resulting reaction solution was stirred for 1 hour and slowly heated to 0° C., the reaction was quenched with water. The reaction solution was brought to pH >7 with 3N aqueous sodium hydroxide solution. Subsequently, the reaction solution was extracted with ethylacetate, washed, dried and purified by column chromatography (hexane:ethylacetate=1:1) to prepare 5.4 mg (20%) of the title compound (compound 12). At this time, 4 mg (40%) of chelidonine was recovered.

[0115]Rf=0.31 (hexane:ethylacetate=1:1)

[0116]1H-...

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Abstract

The present invention relation to a pharmaceutical composition comprising chelidonine or derivatives thereof, with pharmaceutically acceptable carriers. The compositions according to the present invention can selectively block hKv1.5 channels expressed preferentially in human atrial myocytes, and thus are useful as K+ channel blockers and antiarrhythmic drugs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of PCT / KR02 / 00865 filed May 9, 2002 and published in English as WO 02 / 092085 on Nov. 21, 2002 and claims priority from KR application No. 2001-25706 filed May 11, 2001, the entire disclosures of which are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to a composition comprising chelidonine or derivatives thereof, with pharmaceutically acceptable carriers.BACKGROUND ART[0003]Arrhythmias are abnormal rhythms of the heart and cause the heart to pump less effectively. At this time, electro-biochemical properties on local regions of cardiac muscle are changed due to a variety of causes, and thus abnormal cardiac impulse formation or impulse propagation occurs.[0004]The shape and duration of cardiac action potentials vary depending on the region of the heart where they are recorded. These regional differences result, in part, from the differential expression of K+ channel ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4738A61K31/4741A61K9/48A61K47/26A61K9/20A61K9/00C07D491/153A61K9/08A61K31/4355A61K31/58A61P9/06C07J71/00
CPCA61K9/0019A61K31/4741A61K9/2018A61K47/26A61K9/4866A61P9/06A61K31/4355
Inventor EUN, JAE-SOONKWAK, YONG-GEUNKIM, DAE-KEUNCHAE, SOO-WAN
Owner EUN JAE SOON
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